Hemocompatible coated polymer and related one-step methods

ABSTRACT

A polymer with a hemocompatible film or coating is manufactured by a one-step method comprising polymerizing monomer droplets comprising at least one crosslinking agent to form a polymer and simultaneously coating the resulting polymer using at least one dispersing agent to thereby form a hemocompatible coated polymer.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.10/273,249, entitled “Hemocompatible Coated Polymers And RelatedOne-Step Methods” which was filed on Oct. 18, 2002 now U.S. Pat. No.6,885,829.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a polymer with a hemocompatible coatingcomprising at least one crosslinking agent for making the polymer and atleast one dispersing agent whereby the dispersing agent forms ahemocompatible surface coating on the polymer. More specifically, thepresent invention relates to a hemocompatible coated polymermanufactured by a method comprising simultaneously polymerizing andcoating with at least one crosslinking agent for making the polymer andusing at least one dispersing agent to form a hemocompatible coatedpolymer.

2. Description of Related Art

It has been known and practiced in the art of suspension polymerizationto manufacture polymers with a hemocompatible coating using a two-stepprocess. In the first step of the two-step process, polymeric beads aremanufactured by polymerizing monomer droplets using suspensionpolymerization. In the second step of the process, a hemocompatibilizingfilm is applied onto the exterior surface of the polymer to provide thehemocompatible coating. Unlike the prior art, the polymers of thepresent invention are manufactured using a one step process whichutilizes at least one dispersing agent to form a hemocompatible surfacecoating on the polymer.

SUMMARY OF THE INVENTION

The present invention relates to a polymer with a hemocompatible coatingcomprising at least one crosslinking agent for making the polymer and atleast one dispersing agent whereby the dispersing agent forms ahemocompatible surface on the polymer. In one embodiment, the dispersingagent comprises a biocompatibilizing polymer.

In another embodiment, the biocompatibilizing polymer comprisespoly(N-vinylpyrrolidinone). In still another embodiment, thebiocompatibilizing polymer is selected from a group consisting ofpoly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),poly(dimethylaminoethyl methacrylate), salts of poly(acrylic acid),salts of poly(methacrylic acid), poly(diethylaminoethyl methacrylate),poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),poly(N-vinylpyrrolidinone), poly(vinyl alcohol) and mixtures thereof. Inanother embodiment, the salts may be sodium and potassium salts and instill another embodiment, the salts are water-soluble salts.

In yet another embodiment, the dispersing agent is selected from a groupconsisting of hydroxyethyl cellulose, hydroxypopyl cellulose,poly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethylacrylate), poly(diethylamimoethyl methacrylate), poly(diethylaminoethylacrylate), poly(vinyl alcohol), salts of poly(methacrylic acid), andsalts of poly(acrylic acid) and mixtures thereof.

In still another embodiment, the crosslinking agent is selected from agroup consisting of divinylbenzene, trivinylbenzene, divinylnaphthalene,trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate,trimethylolpropane dimethacrylate, trimethylolpropane triacrylate,trimethylolpropane diacrylate, pentaerythrital tetra-, tri-, anddimethacrylates, pentaerythritol tetra-, tri- and diacrylates,dipentaerythritol tetra, tri-, and dimethacrylates, dipentaerythritoltetra-, tri-, and diacrylates, divinylformamide, and mixtures thereof.

In still yet another embodiment, the crosslinking agent comprisesdivinylbenzene. In a further embodiment, the crosslinking agentcomprises trivinylcylohexane. In yet a further embodiment, thecrosslinking agent comprises trivinylbenzene.

In still a further embodiment, the crosslinking agent comprisescopolymers of divinylbenzene with comonomers being selected from a groupconsisting of styrene, ethylstyrene, acrylonitrile, butyl methacrylate,octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate,cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene,vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methylmethacrylate, methyl acrylate and mixtures thereof.

In still yet a further embodiment, the polymer with the hemocompatiblesurface is a porous polymer. In another further embodiment, the polymerwith the hemocompatible surface is an ion exchange polymer. In a furtherembodiment, the polymer is an affinity polymer. In yet another furtherembodiment, the biocompatibilizing polymer becomes grafted to thesurface of the polymer to provide a polymer with the hemocompatiblesurface. For purposes of this invention, the term “grafting” is definedas chemically bonded with potential entanglement such that thedispersing agent is physically restricted from leaving the surface ofthe polymer.

In another embodiment, the present invention relates to a polymermanufactured by a process comprising: simultaneously polymerizing andcoating with at least one crosslinking agent for making the polymer andusing at least one dispersing agent to form a hemocompatible coatedpolymer.

For purposes of this invention, the term “hemocompatibility” is definedas a condition whereby a material, when placed in contact with wholeblood and blood components or physiological fluids, results inclinically acceptable physiological changes. In another embodiment, thedispersing agent is a biocompatibilizing polymer. A “biocompatibilizingpolymer” is defined as a polymer, which forms a surface over anon-biocompatible material, making the polymeric system compatible withphysiological fluids and tissues. The term “crossliking agent” isdefined as a linking agent such as a polyfunctional monomer that linkstwo or more polymer chains or segments of the same polymer chaintogether. The term “dispersing agent” is defined as a substance thatimparts a stabilizing effect upon a finely divided array of immiscibleparticles suspended in a fluidizing medium. The immiscible particles canbe a solid, liquid or gas and the fluidizing medium can be a liquid or agas.

In another embodiment, the crosslinking agent is polymerized with atleast one vinyl monomer. In a further embodiment, the dispersing agentforms a hemocompatible coating on a surface of the polymer. In yet afurther embodiment, the coating of the polymer is equivalent to thesurface of the polymer.

In another embodiment, the dispersing agent comprises abiocompatibilizing polymer. In still another embodiment, thebiocompatibilizing polymer is poly(N-vinylpyrrolidinone). In anotherembodiment, the biocompatibilizing polymer is poly(vinyl alcohol). Inyet another embodiment, the biocompatibilizing polymer is selected froma group consisting of poly(hydroxyethyl methacrylate), poly(hydroxyethylacrylate), poly(dimethylaminoethyl methacrylate), salts of poly(acrylicacid), salts of poly(methacrylic acid), poly(diethylaminoethylmethacrylate), poly(hydroxypropyl methacrylate), poly(hydroxypropylacrylate), poly(N-vinylpyrrolidinone), poly(vinyl alcohol) and mixturesthereof. For purposes of this invention, any biocompatibilizing polymerthat can function as a dispersant can be used in accordance with thisinvention.

In a further embodiment, the dispersing agent is selected from a groupconsisting of hydroxyethyl cellulose, hydroxypopyl cellulose,poly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethylacrylate), poly(diethylamimoethyl methacrylate), poly(diethylaminoethylacrylate), poly(vinyl alcohol), salts of poly (methacrylic acid), andsalts of poly(acrylic acid) and mixtures thereof.

In still a further embodiment, the crosslinking agent is selected from agroup consisting of divinylbenzene, trivinylbenzene, divinylnaphthalene,trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate,trimethylolpropane dimethacrylate, trimethylolpropane triacrylate,trimethylolpropane diacrylate, pentaerythrital tetra-, tri-, anddimethacrylates, pentaerythritol tetra-, tri- and diacrylates,dipentaerythritol tetra, tri-, and dimethacrylates, dipentaerythritoltetra-, tri-, and diacrylates, divinylformamide and mixtures thereof. Inyet a further embodiment, the crosslinking agent comprisesdivinylbenzene. In still a further embodiment, the crosslinking agentcomprises trivinylbenzene. In still another further embodiment, thecrosslinking agent comprises divinylnaphthalene. In yet another furtherembodiment, the crosslinking agent comprises trivinylcylohexane.

In still yet a further embodiment, the crosslinking agent comprisescopolymers of divinylbenzene with comonomers selected from a groupconsisting of styrene, ethylstyrene, acrylonitrile, butyl methacrylate,octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate,cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene,vinylnaphthalene, vinylbenzyl alcohol, vinylformamide and mixturesthereof.

In still a further embodiment, the polymer is processed in non-pyrogenicwater. For purposes of this invention, “non-pyrogenic” shall be definedby U.S.P. 25, Monograph (151) Pyrogenic Test, U.S. Pharmacopeia NationalFormulary.

In still yet another embodiment, the polymer of the present invention isprepared by suspension polymerization. For purposes of the invention,suspension polymerization is defined as the polymerization of monomerdroplets dispersed in an immiscible liquid. Based upon an ElementalAnalysis of the Polymer's Surface by X-Ray Photoelectron Spectroscopy(XPS), the dispersing agent becomes chemically grafting onto the surfaceof the polymer as the monomer droplets are transformed into polymericbeads. Polymers coated with poly(N-vinylpyrrolidinone) have been foundto be biocompatible and hemocompatible. The hemocompatible polymers ofthe present invention pass the Lee White clotting tests and the testsfor the hemolysis of red blood cells.

In another embodiment, the polymer of the present invention is a porouspolymer. The term “porous polymer” is defined as a polymer particlehaving an internal pore structure with a porosity resulting from voidsor holes throughout the polymer matrix. In still another embodiment, thepolymer is an ion exchange resin or polymer. An ion exchange resin orpolymer is a resin or polymer carrying ionogenic groups that are capableof exchanging ions or of sequestering ions. The ion exchange polymers ofthe present invention are beneficial when used with blood for removingand isolating varying ions and ionogenic molecules.

In still yet another embodiment, the present invention relates to apolymer with a hemocompatibilizing surface coating. In a furtherembodiment, the coated polymer is manufactured by a one step processcomprising: simultaneously coating and polymerizing monomer droplets ina suspension polymerization procedure with at least one dispersing agenthaving encapsulated the droplets with a hemocompatible coating tothereby form a polymer with a hemocompatible surface-coating graftedonto the surface of the polymer beads.

In another further embodiment, the dispersing agent comprises abiocompatibilizing polymer. In still a further embodiment, thebiocompatibilizing polymer is poly(N-vinylpyrrolidinone). In yet afurther embodiment, the biocompatibilizing polymer is selected from agroup consisting of poly(hydroxyethyl methacrylate), poly(hydroxyethylacrylate), poly(dimethylaminoethyl methacrylate), salts of poly(acrylicacid), salts of poly(methacrylic acid), poly(diethylaminoethylmethacrylate), poly(hydroxypropyl methacrylate), poly(hydroxypropylacrylate), poly(N-vinylpyrrolidinone), poly(vinyl alcohol) and mixturesthereof In still yet a further embodiment, the polymer geometrycomprises beads, spheroids, pellets, granules and mixtures thereof.

In a further embodiment, the monomer droplets are selected from a groupconsisting of divinylbenzene, styrene, ethylstyrene, acrylonitrile,butyl acrylate, butyl methacrylate, vinyltoluene, vinylnaphthalene,octyl methacrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate,ethyl methacrylate, ethyl acrylate, vinylbenzyl alcohol, vinylformamideand mixtures thereof.

In another embodiment, the present invention relates to a method ofmanufacturing a biocompatible and hemocompatible surface coated polymer.In still another embodiment, the method comprises: polymerizing monomerdroplets comprising at least one crosslinking agent and simultaneouslycoating the resulting polymer beads using at least one dispersing agentto form a biocompatible surface coated polymer. In still anotherembodiment, the coated polymers are hemocompatible. In yet anotherembodiment, the polymer is formed using a suspension polymerizationprocedure. In another embodiment, the polymer is formed using anemulsion polymerization procedure followed by growing the particles withadditional monomer feed.

In still another embodiment, the present invention relates to anapplication of use whereby the hemocompatible surface coated polymers ofthe present invention are utilized for medical applications. In anotherembodiment, the hemocompatible polymers of the present invention may beused to isolate and/or remove target substances from blood andphysiological fluids and for specific treatments. In a furtherembodiment, the hemocompatible polymers of the present invention may beused in preserving organs. In yet another embodiment, the presentinvention relates to an apparatus for isolating blood components and forpurifying blood using the hemocompatible surface coated polymers of thepresent invention. In one embodiment, the apparatus comprises acartridge containing the hemocompatible polymers of the presentinvention.

In yet a further embodiment, the present invention relates to a polymerwith a hemocompatible surface coating, the polymer being manufactured bya method comprising: polymerizing monomer droplets comprising at leastone crosslinking agent to form a polymer and developing a surfacecoating on the polymer by using at least one dispersing agent carryinghydroxyl groups followed by a reaction of hydroxyl groups with a vinylmonomer or polymer to thereby form the hemocompatible surface coating onthe polymer.

In still yet a further embodiment, the present invention also relates toa method of manufacturing a hemocompatible surface coated polymer usinga one step process, the method comprising: polymerizing monomer dropletscomprising at least one crosslinking agent to form a polymer anddeveloping a surface coating on the polymer by using at least onedispersing agent carrying hydroxyl groups followed by a reaction ofhydroxyl groups with a vinyl monomer or polymer to thereby form thehemocompatible surface coating on the polymer.

In another embodiment, the present invention relates to a polymer havinga hemocompatible-coated surface, the polymer being manufactured by atwo-step process comprising: polymerizing monomer droplets comprising atleast one crossliking agent and at least one dispersing agent to form apolymer; and coating the surface of the polymer by crosslinking amonovinyl monomer and a polyfunctional monomer mixture over the surfaceof the polymer bead to thereby form the hemocompatible coating on thesurface of the polymer.

In a further embodiment, the present invention relates to a methodcomprising: polymerizing monomer droplets comprising at least onecrosslinking agent and at least one dispersing agent to form a polymer;and coating the surface of the polymer by crosslinking a monovinylmonomer and a polyfunctional monomer mixture over the surface of thepolymer bead to thereby form the hemocompatible coating on the surfaceof the polymer.

In another embodiment, the present invention relates to a hemocompatiblesystem comprising an organic phase and an aqueous phase, wherein theorganic phase composed of the polymerizable monomers and the porogen aredispersed into a slurry of droplets by agitation throughout the aqueousphase which is formulated to effect the stability of the droplets by thewater-miscible dispersant and to quench polymer growth in the aqueousphase by carrying a water-soluble free radical inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

As required, detailed embodiments of the present invention are disclosedherein; however, it is to be understood that the disclosed embodimentsare merely exemplary of the invention that may be embodied in variousforms. The figures are not necessary to scale, some features may beexaggerated to show details of particular components. Therefore,specific structural and functional details disclosed herein are not tobe interpreted as limiting, but merely as a basis for the claims and asa representative basis for teaching one skilled in the art to variouslyemploy the present invention.

The specific example below will enable the invention to be betterunderstood. However, they are given merely by way of guidance and do notimply any limitation.

EXAMPLE 1

The first polymer synthesis was targeted at an aqueous to organic volumeratio of 1.0. Table 1 below illustrates the targeted dispersion mixturedesigned for Example 1 using a fifty (50) liter reaction.

TABLE 1 Dispersion Mixture Desires for 50 Liters Aqueous/Organic VolumeRatio 1.0 Volume of Organic Phase, ml 25,000.0 Volume of Aqueous Phase,ml 25,000.0 Density of Organic Phase, g/ml 0.83490 Weight of OrganicPhase, g 20,872.5 Density of Aqueous Phase, g/ml 1.005 Weight of AqueousPhase, g 25,125.0 Polymerizable Monomers, DVB plus EVB, g 8766.45 TotalVolume of Organic & Aqueous Phases, ml 50,000.0 Total Weight of Organic& Aqueous Phases, g 45,997.5

The procedure for the polymerization in Example 1 is initiated by thepreparation of an aqueous phase and an organic phase. Table 2 and 3below illustrate the components of the aqueous phase composition for thepolymer synthesis by weight percent (%) and by quantity of thecomponents in grams (g), respectively.

TABLE 2 Aqueous Phase Composition Ultrapure Water, wt. % 98.089 Waterfrom Aqueous 45% Solution of 0.611 Poly(N-vinylpyrrolidinone), wt. %Poly(N-vinylpyrrolidinone) Pure, wt. % 0.500 Sodium Carbonate, wt. %0.500 Sodium Nitrite, wt. % 0.300

Other dispersants, such as poly(vinyl alcohol) have been used as asubstitute for the poly(N-vinylpyrrolidinone).

TABLE 3 Aqueous Phase Charges Ultrapure Water, g 24,644.83 Water fromAqueous 45% Solution of (153.542) Poly(N-vinylpyrrolidinone), gPoly(N-vinylpyrrolidinone) Pure, g (125.625) AqueousPoly(N-vinylpyrrolidinone) Solution, 279.167 45 wt. %, g SodiumCarbonate, g 125.625 Sodium Nitrite, g 75.375 Weights in parenthesis arepart of other charged materials Total Weight of Aqueous Phase, g25,124.997

Table 4 and 5 illustrate the components of the organic phase compositionfor the polymer synthesis by weight percent (5) and by quantity of thecomponents in grams (g), respectively.

TABLE 4 Organic Phase Composition Divinylbenzene (DVB), wt. % 26.998Ethylvinylbenzene (EVB), wt. % 15.0024 Inerts, wt. % 0.41567 Toluene,wt. % 27.134 Isooctane, wt. % 30.450 Benzoyl Peroxide, wt. % ofpolymerizable monomers 1.03

Other immiscible porogens such as isooctane, cyclohexane and nonane havebeen substituted, both singularly and in combination with one another,for the mixture of toluene and isooctane.

TABLE 5 Organic Phase Charges Divinylbenzene, Pure, g (5635.069)Ethylvinylbenzene, Pure, g (3131.381) Commercial DVB, Dow 63.5%, g8853.211 Inerts, g (86.761) Toluene, g 5663.613 Isooctane, g 6355.676Weights in parenthesis are part of commercial DVB Total Weight ofOrganic Phase, g (excluding BPO) 20,872.50 Benzoyl Peroxide, BPO, Pure,g 90.294 75 weight percent BPO, g 120.393 97 weight oercent BPO, g93.087

Upon preparation of the aqueous and organic phases, the aqueous phase isintroduced into the reactor. The reactor is set at an agitation rate ofapproximately 86 revolutions per minute. The aqueous phase is thenheated to 65 degrees Celsius with agitation and a nitrogen sweep throughthe headspace in order to displace oxygen from the reactor space. Theorganic phase is then introduced into the reactor by pouring or pumpingthe organic phase onto the aqueous phase under agitation at a stirringrate of at least 86 revolutions per minute. The droplet dispersion isthen stirred at 86 revolutions per minute for at least fifteen (15)minutes to set the droplet size and allow the droplet slurry toequilibrate as the temperature is raised from about 65 degrees to about70 degrees Celsius. Once the droplet dispersion is homogenous throughoutthe reaction volume, the slurry is then heated to about 75 plus or minus2.0 degrees Celsius and held at that temperature for ten (10) hours.

The slurry is cooled to about 70 degrees Celsius and the stirrer isturned off, and the polymer beads are allowed to collect at the top ofthe fluid bed. The mother liquor is then removed from the bottom of thereactor via a pump until the bead bed approaches within about one (1)inch from the bottom of the reactor. The mother liquor is discarded.

A sufficient amount of ultrapure water at ambient temperature is addedto fluidize the bead bed. The quality of water needed to wash the beadswill be approximately one (1) bed volume or about 25 liters of water.Upon adding the water, the stirrer is then restarted and agitated at astir rate of 106 revolutions per minute for about five (5) minutes. Thestirring is stopped and the beads are allowed to collect at the top ofthe fluid bed.

The liquor is then drained from the bottom of the reactor via a pumpuntil the bead bed approaches within about one (1) inch from the bottomof the reactor. The wash liquor is discarded. The beads are then washedwith the ultrapure water for at least five (5) washes or until the bulkfluid is transparent and free of junk polymer (a clear liquor isachieved). The water-wet bead slurry is transferred to a column that isfitted with a solid-liquid separator at the bottom of the column. Theseparator may be a mesh or screen made from Teflon, nylon,polypropylene, stainless steel, or glass with pore openings in the sizefrom about 100 to about 300 microns.

The porogen mixture is displaced from the beads by a downflow treatmentwith ten (10) bed volumes of isopropyl alcohol at a flow rate of one (1)bed volume per hour. The isopropyl alcohol is displaced from the beadswith water at a downflow treatment with ten (10) bed volumes ofultrapure water (pyrogen and endotoxin free) at a flow rate of one (1)bed volume per hour. The polymer beads are then transferred from thecolumn into plastic containers for transport to the thermal steam-fluxcleaner.

EXAMPLE 2

Experiments were performed using the polymer beads manufactured by thepolymerization procedures described in Example 1 and the measuredresults on the polymer products are illustrated in Tables 6–7 set forthbelow:

TABLE 6 Experimental Program: Input Sample Sample Sample Sample SampleSample Sample Sample Sample Sample Sample ID ID ID ID ID ID ID ID ID IDID LDM 02-001 02-004 02-006 02-008 02-010 02-012 02-015 02-016 02-01702-022 02-025 Organic phase Composition Monomer (DVB &EVB) Wt. % 42.042.0 42.0 42.0 40.7 50.0 40.0 40.0 45.0 45.0 45.0 Porogen Wt. % 58.058.0 58.0 58.0 59.3 50.0 60.0 60.0 55.0 55.0 55.0 Porogen/Monomer Ratio1.3810 1.3810 1.3810 1.3810 1.457 1.000 1.500 1.500 1.222 1.222 1.222Benzoyl Peroxide (BPO) 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.031.03 Wt. % Porogen Composition Isooctane, Wt. % 52.5 52.5 52.5 52.5 53.560.0 99.327 99.327 99.174 99.174 99.174 Toluene, Wt. % 46.769 46.76946.769 46.769 45.81 38.99 0 0 0 0 0 Inerts, Wt. % 0.731 0.731 0.7310.731 0.693 1.010 0.6734 0.826 0.826 0.826 0.726 Toluene plus Inerts,Wt. % 47.5 47.5 47.5 47.5 46.5 40.0 — — — — — Isooctane/Toluene plusInerts 1.105 1.105 1.105 1.105 1.1505 1.500 — — — — — Ratio Aquoeusphase Composition Sodium Carbonate, Wt. % 0.500 0.500 0.500 0.500 0.5000.500 0.500 0.500 0.500 0.500 0.500 Sodium Nitrate, Wt. % 0.300 0.3000.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300Poly(N-Vinylpyrrolidione) Wt. % 0.500 0.500 0.450 0.400 0.400 0.4000.100 0.400 0.500 0.500 1.000 PVP K 30, 45–55 Kdaltons, 0 0 0 0 0 0 0 00 0.250 1.000 Wt. % PVP K 60,400–500 Kdaltons, 0.500 0.500 0.450 0.4000.400 0.400 0.100 0.400 0.500 0.250 0 Wt. % Poly(Vinyl alcohol), Wt. %0.01 0.01 0.05 0.100 0.100 0.100 0.400 0.100 0 0 0 Molecular Size,Kdaltons 88.0 88.0 95.0 95.0 95.0 95.0 95.0 95.0 — — — AmountHydrolyzed, % 85 85 95 95 95 95 95 95 — — — Aqueous/Organic Phase 0.90.9 0.9 0.9 0.9 0.9 0.9 0.9 0.9 1.1 1.1 Volume Ratio Sample SampleSample Sample Sample Sample Sample Sample Sample Sample Sample Sample IDID ID ID ID ID ID ID ID ID ID ID LDM 02-028 02-029 02-030 02-031 02-03202-033 02-034 02-036 02-038 02-040 02-042 02-044 Organic PhaseComposition Monomer (DVB &EVB) Wt. % 45.0 45.0 45.0 45.0 45.0 50.0 55.055.0 55.0 55.0 55.0 55.0 Porogen Wt. % 55.0 55.0 55.0 55.0 55.0 50.045.0 45.0 45.0 45.0 45.0 45.0 Porogen/Monomer Ratio 1.222 1.222 1.2221.222 1.222 1.000 0.8182 0.8182 0.8182 0.8182 0.8182 0.8182 BenzoylPeroxide (BPO) 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.031.03 Wt. % Porogen Compostion Isooctane, Wt.. % 99.274 99.274 99.27499.274 99.274 99.1122 98.915 98.915 98.915 98.915 98.915 98.915 Toluene,Wt. % 0 0 0 0 0 0 0 0 0 0 0 0 Inerts, Wt. % 0.726 0.726 0.726 0.7260.726 0.8878 1.085 1.085 1.085 1.085 1.085 1.085 Toluene plus Inerts,Wt. % — — — — — — — — — — — — Isooctane/Toluene plus Inerts — — — — — —— — — — — — Ratio Aqueous Phase Composition Sodium Carbonate, Wt. %0.500 0.500 0.500 0.500 0.500 0.500 0.500 0.500 0.500 0.500 0.500 0.500Sodium Nitrate, Wt. % 0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.3000.300 0.300 0.300 0.300 Poly(N-Vinylpyrrolidione) Wt. % 0.700 0.9001.000 1.000 1.500 1.000 0.500 1.300 1.100 1.000 0.200 0.300 PVP K 30,45–55 Kdaltons, 0.700 0.900 1.000 1.000 1.500 0.900 0 1.000 1.000 0.8000 0 Wt. % PVP K 60, 400–500 Kdaltons, 0 0 0 0 0 0.100 0.500 0.300 0.1000.200 0.200 0.300 Wt. % Poly(Vinyl alcohol), Wt. % 0 0 0 0 0 0 0 0 0 0 00 Molecular Size, Kdaltons — — — — — — — — — — — — Amount Hydrolysed, %— — — — — — — — — — — — Aqueous/Organic Phase 1.2 1.2 1.145 1.2 1.2 1.11.1 1.0 1.0 1.0 1.0 1.0 Volume Ratio Sample Sample Sample Sample SampleSample Sample Sample Sample Sample Sample Sample ID ID ID ID ID ID ID IDID ID ID ID LDM 02-047 02-049 02-050 02-052 02-054 02-055 02-059 02-06102-073 02-074 02-075 02-079 Organic Phase Composition Monomer (DVB &EVB)Wt. % 55.0 55.0 55.0 55.0 55.0 55.0 55.0 55.0 55.0 55.0 55.0 55.0Porogen Wt. % 45.0 45.0 45.0 45.0 45.0 45.0 45.0 45.0 45.0 45.0 45.045.0 Porogen/Monomer Ratio 0.8182 0.8182 0.8182 0.8182 0.8182 0.81820.8182 0.8182 0.8182 0.8182 0.8182 0.8182 Benzoyl Peroxide (BPO) 1.031.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 1.03 Wt. % PorogenComposition Isooctane, Wt. % 98.915 98.915 98.915 98.915 98.915 98.91598.915 98.915 98.915 98.915 98.915 98.915 Toluene, Wt. % 0 0 0 0 0 0 0 00 0 0 0 Inerts, Wt. % 1.085 1.085 1.085 1.085 1.085 1.085 1.085 1.0851.085 1.085 1.085 1.085 Toluene plus Inerts, Wt. % — — — — — — — — — — —— Isooctane/Toluene plus Inerts — — — — — — — — — — — — Ratio AqueousPhase Composition Sodium Carbonate, Wt. % 0.300 0.100 0.500 0.500 0.5000.500 0.500 0.500 0.500 0.500 0.500 0.500 Sodium Nitrate, Wt. % 0.3000.100 0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300Poly(N-Vinylpyrrolidione) Wt. % 0.010 0.010 0 0.05 0 0 0 0 0 0 0 0 PVP K30, 45–55 Kdaltons, 0.010 0.010 0 0.05 0 0 0 0 0 0 0 0 Wt. % PVP K 60,400–500 Kdaltons, 0 0 0 0 0 0 0 0 0 0 0 0 Wt. % Poly(Vinyl alcohol), Wt.% 0.250 0.400 0 0 0 0 0.300 0.300 0.300 0.300 0.300 0.300 MolecularSize, Kdaltons 95 95 — — — — 170 170 170 170 170 170 Amount Hydrolyzed,% 95 95 — — — — 88 88 88 88 88 88 Natrosol Plus, Wt. % 0 0 0.500 0.3000.300 0.300 0 0 0 0 0.05 0 Aqueous/Organic Phase 1.0 1.0 1.0 1.0 1.0 1.01.0 1.0 1.0 1.0 1.0 1.0 Volume Ratio Sample Sample Sample ID ID IDSample Sample Sample Sample Sample Sample Sample Sample Sample LDM02-082 02-083 02-086 ID ID ID ID ID ID ID ID ID Organic PhaseComposition Monomer (DVB &EVB) Wt. % 55.0 55.0 55.0 Porogen Wt. % 45.045.0 45.0 Porogen/Monomer Ratio 0.8182 0.8182 0.8182 Benzoyl Peroxide(BPO) 1.03 1.03 1.03 Wt. % Porogen Composition Isooctane, Wt. % 98.91598.915 98.915 Toluene, Wt. % 0 0 0 Inerts, Wt. % 1.085 1.085 1.085Toluene plus Inerts, Wt. % — — — Isooctane/Toluene plus Inerts — — —Ratio Aqueous Phase Composition Sodium Carbonate, Wt. % 0.500 0.5000.500 Sodium Nitrate, Wt. % 0.300 0.300 0.300 Poly(N-Vinylpyrrolidione)Wt. % 0 0 0 PVP K 30, 45–55 Kdaltons, 0 0 0 Wt. % PVP K 60, 400–500Kdaltons, 0 0 0 Wt. % Poly(Vinyl alcohol), Wt. % 0.300 0.300 0.300Molecular Size, Kdaltons 170 100 170 Amount Hydrolyzed, % 88 85 88Natrosol Plus, Wt. % 0 0 0 Aqueous/Organic Phase 1.0 1.0 1.0 VolumeRatio

TABLE 7 Experimental Programs: Responses Sample ID Sample ID Sample IDSample ID Sample ID LDM-02-001 LDM-02-004 LDM-02-006 LDM-02-008LDM-02-010 Surface Characteristics SEM; description (smooth, nodes,nodes, nodes, nodes, nodes, nodes present, open or closed pore closedclosed closed closed closed structure) Internal Pore Structure BETSurface Area, S 563.5001 652.7807 615.7039 614.4325 661.4491 Porosity,Pwt in ml · g -1 0.921032 1.536987 1.530853 1.724477 1.772158 Pore modesgreater than 100 A 150 250, 400 200, 600 450, 550 500 Diameter fromdesorption Isotherm. List each Pore modes range in A greater 100–250100–500 100–700 100–700 100–600 than 100 A diameter, desorptionIsotherm. Particle Size Distribution Unclassified, directly from reactorCytonchrome C Sorption Static Assessment 500 mg/Liter Conc. Mg cyto csorbed/g 15.2 43.35 42.95 63.05 79.7 dry polymer at 3 hr contact % ofcyto C removed from 19.23 53.8 51.46 66.22 73.78 solution at 3 hrcontact Serum Albumin Sorption % removed from solution with aconcentration of 35,000 mg/l of serum albumin Mg BSA(or HSA) sorbed/gdry polymer at 3 hr contact Coating Assessment ESCA Measurements forSurface Components Atom Fraction on surface C 0.8702 0.8722 0.89170.8881 0.8855 O 0.0784 0.0758 0.0682 0.0729 0.086 N 0.0514 0.052 0.04010.039 0.0284 Sample ID Sample ID Sample ID Sample ID Sample IDLDM-02-017 LDM-02-025 LDM-02-034 LDM-02-036 LDM-02-038 SurfaceCharacteristics SEM; description (smooth, no nodes, no nodes, no nodes,no nodes, nodes nodes present, open or closed pore open open open openclosed structure) Internal Pore Structure BET Surface Area, S 519.8904539.9826 537.1961 556.5873 556.5738 Porosity, Pwt in ml · g -1 1.2408851.389936 1.906947 1.958844 1.875443 Pore modes greater than 100 A 250,310, 320, 450 380, 490 210, 280 210, 280, Diameter from desorption 430,550,  550, 750, 750, 950  380, 500, 380 Isotherm. List each 750 1200,1700 650 500, 650, 1200, 1800 910 1600 Pore modes range in A greater100–1900 100–1800 100–1600 100–1600 100–1600 than 100 A diameter,desorption Isotherm. Particle Size Distribution Unclassified, directlyfrom reactor Cytonchrome C Sorption Static Assessment 500 mg/Liter Conc.Mg cyto c sorbed/g 135.9 155.8 86.6 82.0 72.4 dry polymer at 3 hrcontact % of cyto C removed from 82.64 82.49 85.12 85.26 68.78 solutionat 3 hr contact Serum Albumin Sorption % removed from solution with 6.04.1 5.1 a concentration of 35,000 mg/l of serum albumin Mg BSA(or HSA)sorbed/g dry polymer 1681.7 313.9 328.1 at 3 hr contact CoatingAssessment ESCA Measurements for Surface Components Atom Fraction onsurface C 0.6476 0.6134 0.8981 0.8682 0.8901 O 0.0795 0.1178 0.07780.935 0.0771 N 0.0281 none 0.0241 0.0383 0.0328 detected Sample IDSample ID Sample ID Sample ID LDM- Sample ID LDM-02-040 LDM-02-044LDM-02-054 02-055A LDM-02-075 Cytonchrome C Sorption Static Assessment500 mg/Liter Conc. Mg cyto c sorbed/g 57.6 61.7 73.9 57.8 dry polymer at3 hr contact % of cyto C removed from 61.4 65.5 79.8 63.6 solution at 3hr contact Serum Albumin Sorption % removed from solution with 3.1 aconcentration of 35,000 mg/l of serum albumin Mg BSA(or HSA) sorbed/gdry polymer 203.1 at 3 hr contact Coating Assessment ESCA Measurementsof Surface Components Atom Fraction on surface C 0.8586 0.8748 0.82380.7924 O 0.0982 0.0897 0.1745 0.2076 N 0.0432 0.0355 none none detecteddetected Surface Characteristics SEM; description (smooth, nodes, nodes,nodes, nodes present, open or closed pore closed closed closedstructure) Internal Pore Structure BET Surface Area, S 549.64 545.38536.79 525.15 531.47 Porosity, Pwt in ml · g -1 1.8356 1.642 1.65671.6957 1.5232 Pore modes greater than 100 A 300; 400; 250; 310; 200;300; 300; 400; 200; 300; Diameter from desorption 500; 650; 450; 620;400; 500; 600; 750; 420; 550; Isotherm. List each 850 800; 1200 650; 920900 750; 900; 1200 Pore modes range in A greater 300–980 200–1300200–1700 150–1300 100–1300 than 100 A diameter, desorption Isotherm.Particle Size Distribution Unclassified, directly from reactor Sample IDSample ID Sample ID Sample ID LDM-02-079 LDM-02-082 LDM-02-083LDM-02-086 Sample ID Cytonchrome C Sorption Static Assessment 500mg/Liter Conc. Mg cyto c sorbed/g 61.1 dry polymer at 3 hr contact % ofcyto C removed from 74.9 solution at 3 hr contact Serum Albumin Sorption% removed from solution with a concentration of 35,000 mg/l of serumalbumin Mg BSA(or HSA) sorbed/g dry polymer at 3 hr contact CoatingAssessment ESCA Measurements of Surface Components Atom Fraction onsurface C O N Surface Characteristics SEM; description (smooth, nodespresent, open or closed pore structure) Internal Pore Structure BETSurface Area, S 528.93 Porosity, Pwt in ml · g -1 1.3708 Pore modesgreater than 100 A 250; 300; Diameter from desorption 400; 500;Isotherm. List each 600; 750;  900; 1300  Pore modes range in A greater100–1400 than 100 A diameter, desorption Isotherm. Particle SizeDistribution Unclassified, directly from reactor

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the attendant claims attachedhereto, this invention may be practiced otherwise than as specificallydisclosed herein.

1. A hemocompatible-coated polymer comprising at least one crosslinkingagent and at least one dispersing agent whereby said dispersing agentforms a hemocompatible surface on said polymer, said dispersing agent isselected from a group consisting of hydroxyethyl cellulose, hydroxypopylcellulose, poly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethylacrylate), poly(diethylamimoethyl methacrylate), poly(diethylaminoethylacrylate), poly(vinyl alcohol), poly(N-vinylpyrrolidinone), salts ofpoly(methacrylic acid), and salts of poly(acrylic acid) and mixturesthereof, said crosslinking agent is selected from a group consisting ofdivinylbenzene, trivinylbenzene, divinylnaphthalene,trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate,trimethylolpropane dimethacrylate, trimethylolpropane triacrylate,trimethylolpropane diacrylate, pentaerythrital dimethacrylates,pentaerythrital trimethacrylates, pentaerythrital, tetramethacrylates,pentaerythritol diacrylates, pentaerythritol triiacrylates,pentaerythritol tetraacrylates, dipentaerythritol dimethacrylates,dipentaerythritol trimethacrylates, dipentaerythritoltetramethacrylates, dipentaerythritol diacrylates, dipentaerythritoltriacrylates, dipentaerythritol tetraacrylates, divinylformamide andmixtures thereof, said polymer being developed simultaneously with theformation of the coating, wherein said dispersing agent gets chemicallybound to said surface of said polymer.
 2. The polymer of claim 1 claimsaid dispersing agent comprises a biocompatibilizing polymer.
 3. Thepolymer of claim 2 claim said biocompatibilizing polymer comprisespoly(N-vinylpyrrolidinone).
 4. The polymer of claim 2 claim saidbiocompatibilizing polymer becomes grafted to the surface of saidpolymer to provide said hemocompatible surfaced polymer.
 5. The polymerof claim 1 claim said polymer comprises copolymers of divinylbenzenewith comonomers being selected from a group consisting of styrene,ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate,butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate,ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene,vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methylacrylate and mixtures thereof.
 6. The polymer of claim 1 claim saidhemocompatible surfaced polymer is a porous polymer.
 7. The polymer ofclaim 1 claim said hemocompatible surfaced polymer is an ion exchangepolymer.
 8. A biocompatible coated polymer manufactured by a methodcomprising: polymerizing monomer droplets comprising at least onecrosslinking agent to form a polymer and coating said resulting polymerusing at least one dispersing agent to thereby form a biocompatiblecoated polymer, said dispersant being placed on said monomer dropletsbefore polymerization, said dispersing agent is selected from a groupconsisting of hydroxyethyl cellulose, hydroxypopyl cellulose,poly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethylacrylate), poly(diethylamimoethyl methacrylate), poly-(diethylaminoethylacrylate), poly(vinyl alcohol), poly(N-vinylpyrrolidinone), salts ofpoly(methacrylic acid), and salts of poly(acrylic acid) and mixturesthereof, wherein said dispersing agent gets chemically bound to saidsurface of said polymer.
 9. The polymer of claim 8 claim saidcrosslinking agent is polymerized with at least one vinyl monomer. 10.The polymer of claim 8 claim said dispersing agent forms ahemocompatible coating on the surface of said polymer.
 11. The polymerof claim 8 claim said dispersing agent comprises a biocompatibilizingpolymer.
 12. The polymer of claim 8 wherein said biocompatibilizingpolymer is poly (N-vinylpyrrolidinone).
 13. The polymer of claim 8wherein said biocompatibilizing polymer is poly(vinyl alcohol).
 14. Thepolymer of claim 11 wherein said biocompatibilizing polymer becomesgrafted to the surface of said polymer to provide said hemocompatiblecoated polymer.
 15. The polymer of claim 8 wherein said crosslinkingagent is selected from a group consisting of divinylbenzene,trivinylbenzene, divinylnaphthalene, trivinylcyclohexane,divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropanedimethacrylate, trimethylolpropane triacrylate, trimethylolpropanediacrylate, pentaerythrital dimethacrylates, pentaerythritaltrimethacrylates, pentaerythrital tetramethacrylates, pentaerythritoldiacrylates, pentaerythritol triiacrylates, pentaerythritoltetraacrylates, dipentaerythritol dimethacrylates, dipentaerythritoltrimethacrylates, dipentaerythritol tetramethacrylates,dipentaerythritol diacrylates, dipentaerythritol triacrylates,dipentaerythritol tetraacrylates, divinylformamide and mixtures thereof.16. The polymer of claim 8 wherein said crosslinking agent comprisesdivinylbenzene.
 17. The polymer of claim 8 wherein said crosslinkingagent comprises trivinylcylohexane.
 18. The polymer of claim 8 whereinsaid crosslinking agent comprises trivinylbenzene.
 19. The polymer ofclaim 8 wherein said polymer comprises copolymers of divinylbenzene withcomonomers being selected from a group consisting of styrene,ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate,butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate,ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene,vinylbenzyl alcohol, vinylformamide and mixtures thereof.
 20. Thepolymer of claim 8 wherein said hemocompatible coated polymer is aporous polymer.
 21. The polymer of claim 8 wherein said hemocompatiblecoated polymer is an ion exchange polymer.
 22. The polymer of claim 8wherein said polymer is processed in non-pyrogenic water.
 23. A polymerwith a hemocompatible surface coating, said polymer being manufacturedby a one step process comprising: simultaneously coating andpolymerizing monomer droplets in a suspension polymerization procedurewith at least one dispersing agent having encapsulated said dropletswith a hemocompatible coating to thereby form a polymer with ahemocompatible surface-coating grafted onto the surface of said polymer,said dispersing agent being a biocompatibilizing polymer, saiddispersing agent is selected from a group consisting of hydroxyethylcellulose, hydroxypopyl cellulose, poly(hydroxyethyl methacrylate),poly(hydroxyethyl acrylate), poly(hydroxypropyl methacrylate),poly(hydroxypropyl acrylate), poly(dimethylaminoethyl methacrylate),poly-(dimethylaminoethyl acrylate), poly(diethylamimoethylmethacrylate), poly-(diethylaminoethyl acrylate), poly(vinyl alcohol),poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), and saltsof poly(acrylic acid) and mixtures thereof, wherein said dispersingagent gets chemically grafted to said surface of said polymer.
 24. Thepolymer of claim 23 wherein said monomer droplets is selected from agroup consisting of divinylbenzene, styrene, ethylstyrene,acrylonitrile, butyl acrylate, butyl methacrylate, vinyltoluene,vinylnaphthalene, octyl methacrylate, octyl acrylate, cetylmethacrylate, cetyl acrylate, ethyl methacrylate, ethyl acrylate,vinylbenzyl alcohol, vinylformamide and mixtures thereof.